This proposal describes the synthesis and further study of the monanchocidin family of marine natural products. The monanchocidins have novel chemical structures and potent biological activities making them ideal targets for chemical synthesis. Further, the monanchocidins are active against relevant human cancer cell lines, and related natural products active against a number of diseases, and thereby serve as lead compounds for the development of chemical probes and/or therapeutics. Synthetic access to the monanchocidins has not yet been reported and little is understood regarding their biological targets. The objective of the proposed research is to develop a scalable and expedient approach to the pentacyclic guanidine alkaloids and apply this synthetic scheme to the monanchocidins and related natural products. We plan to achieve this goal by combining a concise and asymmetric synthesis of a linear precursor with a biomimetic guanidine-forming cascade. A stereoselective synthesis of a heavily oxidized morpholine heterocycle that constitutes the eastern half of the natural products is also targeted. In parallel to our syntheti efforts we are investigating the biological activity of the natural product fragments as they become available and have already revealed interesting properties. We plan to advance these scaffolds to potent and selective chemical probes for polyamine signaling pathways and for in-vivo protein modification. We expect that our efforts will lead to significant advances in both synthetic chemistry and chemical biology and reveal rational paths forward for the development of chemical probes.